Effects of PM2.5 exposure on the Notch signaling pathway and immune imbalance in chronic obstructive pulmonary disease
Effects of PM2.5 exposure on the Notch signaling pathway and immune imbalance in chronic obstructive pulmonary disease
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PM2.5暴露对慢性阻塞性肺疾病Notch信号通路及免疫失衡的影响
DOI：
10.1016/j.envpol.2017.03.070
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发表时间：
2017-07-01
影响因子：
8.9
通讯作者：
Liu, Xiao-Ju
中科院分区：
文献类型：
--
作者：
Gu, Xing-yu;Chu, Xu;Liu, Xiao-Ju
慢性阻塞性肺疾病(COPD)与T淋巴细胞亚群(Th1/Th2、Th17/Treg)失衡有关。Notch信号通路在获得性免疫的发展中起着关键作用。细颗粒物(PM2.5)引起的免疫紊乱与COPD有关。本研究的目的是探讨PM2.5影响Notch信号通路导致免疫紊乱恶化和加速COPD发展的机制。通过香烟烟雾暴露建立COPD小鼠模型。PM2.5暴露采用雾化吸入的方法。通过腹腔注射给予γ-分泌酶抑制剂。采用密度梯度离心法纯化脾T淋巴细胞。采用流式细胞仪检测患者外周血中CD4+T细胞亚群(Th1/Th2、Th17/Treg)。用RT-PCR和Western印迹方法检测Notch1/2/3/4、Hes1/5和Heyl的mRNA和蛋白表达。采用双抗体夹心法测定血清干扰素-γ、白介素17、白介素10水平。结果表明，COPD小鼠Th1%、Th17%、Th1/Th2、Th17/Treg显著升高，Notch1/2/3/4、Hes1/5、Heyl的mRNA和蛋白水平及血清干扰素-γ、IL-17浓度显著升高，Th2%、Treg%、血清IL-4、IL-10浓度显著降低。COPD小鼠存在Th1和Th17介导的免疫紊乱，Notch信号通路处于过度激活状态。PM2.5促进Notch信号通路的过度激活，加重COPD的免疫紊乱。GSI可部分抑制Notch信号通路的激活，减轻基础状态下的免疫紊乱和PM2.5引起的COPD免疫紊乱。这一结果提示PM2.5通过影响Notch信号通路参与了COPD小鼠的免疫紊乱，PM2.5加重了COPD。(C)爱思唯尔有限公司发布的2017年。
Chronic Obstructive Pulmonary Disease (COPD) is associated with T lymphocytes subset (Th1/Th2, Th17/Treg) imbalance. Notch signaling pathway plays a key role in the development of the adaptive immunity. The immune disorder induced by fine particulate matter (PM2.5) is related to COPD. The aim of this study was to investigate the mechanism by which PM2.5 influences the Notch signaling pathway leading to worsening immune disorder and accelerating COPD development. A COPD mouse model was established by cigarette smoke exposure. PM2.5 exposure was performed by aerosol inhalation. gamma-secretase inhibitor (GSI) was given using intraperitoneal injection. Splenic T lymphocytes were purified using a density gradient centrifugation method. CD4(+) T lymphocyte subsets (Th1/Th2, Th17/Treg) were detected using flow cytometry. mRNA and proteins of Notch1/2/3/4, Hes1/5, and Heyl were detected using RT-PCR and Western blot. Serum INF-gamma, IL-17 and IL-10 concentrations were measured using ELISA. The results showed that in COPD mice Th1% and Th17%, Th1/Th2 and Th17/Treg were increased, and the levels of mRNA and protein in Notch1/2/3/4, Hes1/5, and Heyl and serum INF-gamma and IL-17 concentrations were significantly increased, and Th2%, Treg%, and serum IL-4 and IL-10 concentrations were significantly decreased. COPD Mice have Th1- and Th17-mediated immune disorder, and the Notch signaling pathway is in an overactivated state. PM2.5 promotes the overactivation of the Notch signaling pathway and aggravates the immune disorder of COPD. GSI can partially inhibit the activation of the Notch signaling pathway and alleviate the immune disorder under basal state and the immune disorder of COPD caused by PM2.5. This result suggests that PM2.5 is involved in the immune disorder of mice with COPD by affecting the Notch signaling pathway and that PM2.5 aggravates COPD. (C) 2017 Published by Elsevier Ltd.